|
1
|
Chuang YT, Yen CY, Tang JY, Chang FR, Tsai YH, Wu KC, Chien TM, Chang HW. The modulation of immune cell death in connection to microRNAs and natural products. Front Immunol 2024; 15:1425602. [PMID: 39759512 PMCID: PMC11695430 DOI: 10.3389/fimmu.2024.1425602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 11/27/2024] [Indexed: 01/07/2025] Open
Abstract
Immunogenic cell death (ICD) spatiotemporally regulates damage-associated molecular patterns (DAMPs) derived from dying cancer cells to signal the immune response. Intriguingly, these DAMPs and cytokines also induce cellular responses in non-immune cells, particularly cancer cells. Several ICD-modulating natural products and miRNAs have been reported to regulate the DAMP, cytokine, and cell death responses, but they lack systemic organization and connection. This review summarizes the impacts of natural products and miRNAs on the DAMP and cytokine responses and cancer cell death responses (apoptosis, autophagy, ferroptosis, necroptosis, and pyroptosis). We establish the rationale that ICD inducers of natural products have modulating effects on miRNAs, targeting DAMPs and cytokines for immune and cancer cell death responses. In conclusion, DAMP, cytokine, and cell death responses are intricately linked in cancer cells, and they are influenced by ICD-modulating natural products and miRNAs.
Collapse
Affiliation(s)
- Ya-Ting Chuang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ching-Yu Yen
- School of Dentistry, Taipei Medical University, Taipei, Taiwan
- Department of Oral and Maxillofacial Surgery, Chi-Mei Medical Center, Tainan, Taiwan
| | - Jen-Yang Tang
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yi-Hong Tsai
- Department of Pharmacy and Master Program, College of Pharmacy and Health Care, Tajen University, Pingtung, Taiwan
| | - Kuo-Chuan Wu
- Department of Computer Science and Information Engineering, National Pingtung University, Pingtung, Taiwan
| | - Tsu-Ming Chien
- School of Post-Baccalaureate Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Department of Urology, Kaohsiung Gangshan Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hsueh-Wei Chang
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
| |
Collapse
|
|
2
|
Toledo-Stuardo K, Ribeiro CH, Campos I, Tello S, Latorre Y, Altamirano C, Dubois-Camacho K, Molina MC. Impact of MICA 3'UTR allelic variability on miRNA binding prediction, a bioinformatic approach. Front Genet 2023; 14:1273296. [PMID: 38146340 PMCID: PMC10749337 DOI: 10.3389/fgene.2023.1273296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 11/13/2023] [Indexed: 12/27/2023] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that participate as powerful genetic regulators. MiRNAs can interfere with cellular processes by interacting with a broad spectrum of target genes under physiological and pathological states, including cancer development and progression. Major histocompatibility complex major histocompatibility complex class I-related chain A (MICA) belongs to a family of proteins that bind the natural-killer group 2, member D (NKG2D) receptor on Natural Killer cells and other cytotoxic lymphocytes. MICA plays a crucial role in the host's innate immune response to several disease settings, including cancer. MICA harbors various single nucleotide polymorphisms (SNPs) located in its 3'-untranslated region (3'UTR), a characteristic that increases the complexity of MICA regulation, favoring its post-transcriptional modulation by miRNAs under physiological and pathological conditions. Here, we conducted an in-depth analysis of MICA 3'UTR sequences according to each MICA allele described to date using NCBI database. We also systematically evaluated interactions between miRNAs and their putative targets on MICA 3'UTR containing SNPs using in silico analysis. Our in silico results showed that MICA SNPs rs9266829, rs 1880, and rs9266825, located in the target sequence of miRNAs hsa-miR-106a-5p, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-20b-5p, hsa-miR-93, hsa-miR-1207.5p, and hsa-miR-711 could modify the binding free energy between -8.62 and -18.14 kcal/mol, which may affect the regulation of MICA expression. We believe that our results may provide a starting point for further exploration of miRNA regulatory effects depending on MICA allelic variability; they may also be a guide to conduct miRNA in silico analysis for other highly polymorphic genes.
Collapse
Affiliation(s)
- Karen Toledo-Stuardo
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Carolina H. Ribeiro
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Ivo Campos
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Samantha Tello
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| | - Yesenia Latorre
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
- School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Claudia Altamirano
- School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Karen Dubois-Camacho
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
- Faculty of Medicine, Clinical and Molecular Pharmacology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
- Gastroenterology and Hepatology Department, University Medical Center Groningen, Groningen, Netherlands
| | - Maria Carmen Molina
- Faculty of Medicine, Immunology Program, Institute of Biomedical Sciences (ICBM), Universidad de Chile, Santiago, Chile
| |
Collapse
|
|
3
|
Zhang J, Luo Q, Li X, Guo J, Zhu Q, Lu X, Wei L, Xiang Z, Peng M, Ou C, Zou Y. Novel role of immune-related non-coding RNAs as potential biomarkers regulating tumour immunoresponse via MICA/NKG2D pathway. Biomark Res 2023; 11:86. [PMID: 37784183 PMCID: PMC10546648 DOI: 10.1186/s40364-023-00530-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 09/24/2023] [Indexed: 10/04/2023] Open
Abstract
Major histocompatibility complex class I related chain A (MICA) is an important and stress-induced ligand of the natural killer group 2 member D receptor (NKG2D) that is expressed in various tumour cells. Given that the MICA/NKG2D signalling system is critically embedded in the innate and adaptive immune responses, it is particularly involved in the surveillance of cancer and viral infections. Emerging evidence has revealed the important roles of non-coding RNAs (ncRNAs) including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) in different cancer types. We searched for all relevant publications in the PubMed, Scopus and Web of Science database using the keywords ncRNA, MICA, NKG2D, cancer, and miRNAs. All relevant studies published from 2008 to the 2023 were retrieved and collated. Notably, we found that miRNAs can target to NKG2D mRNA and MICA mRNA 3'-untranslated regions (3'-UTR), leading to translation inhibition of NKG2D and MICA degradation. Several immune-related MICA/NKG2D pathways may be dysregulated in cancer with aberrant miRNA expressions. At the same time, the competitive endogenous RNA (ceRNA) hypothesis holds that circRNAs, lncRNAs, and mRNAs induce an abnormal MICA expression by directly targeting downstream miRNAs to mediate mRNA suppression in cancer. This review summarizes the novel mechanism of immune escape in the ncRNA-related MICA/NKG2D pathway mediated by NK cells and cancer cells. Moreover, we identified the miRNA-NKG2D, miRNA-MICA and circRNA/lncRNA/mRNA-miRNA-mRNA/MICA axis. Thus, we were particularly concerned with the regulation of mediated immune escape in the MICA/NKG2D pathway by ncRNAs as potential therapeutic targets and diagnostic biomarkers of immunity and cancer.
Collapse
Affiliation(s)
- Jing Zhang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Qizhi Luo
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Xin Li
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Junshuang Guo
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Quan Zhu
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Xiaofang Lu
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Leiyan Wei
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Zhiqing Xiang
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Manqing Peng
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China
| | - Chunlin Ou
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410000, Hunan, China.
| | - Yizhou Zou
- Department of Immunology, School of Basic Medicine, Central South University, Changsha, 410000, Hunan, China.
| |
Collapse
|
|
4
|
Otmani K, Rouas R, Lewalle P. OncomiRs as noncoding RNAs having functions in cancer: Their role in immune suppression and clinical implications. Front Immunol 2022; 13:913951. [PMID: 36189271 PMCID: PMC9523483 DOI: 10.3389/fimmu.2022.913951] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Currently, microRNAs have been established as central players in tumorigenesis, but above all, they have opened an important door for our understanding of immune and tumor cell communication. This dialog is largely due to onco-miR transfer from tumor cells to cells of the tumor microenvironment by exosome. This review outlines recent advances regarding the role of oncomiRs in enhancing cancer and how they modulate the cancer-related immune response in the tumor immune microenvironment.MicroRNAs (miRNAs) are a type of noncoding RNA that are important posttranscriptional regulators of messenger RNA (mRNA) translation into proteins. By regulating gene expression, miRNAs enhance or inhibit cancer development and participate in several cancer biological processes, including proliferation, invasion metastasis, angiogenesis, chemoresistance and immune escape. Consistent with their widespread effects, miRNAs have been categorized as oncogenes (oncomiRs) or tumor suppressor (TS) miRNAs. MiRNAs that promote tumor growth, called oncomiRs, inhibit messenger RNAs of TS genes and are therefore overexpressed in cancer. In contrast, TS miRNAs inhibit oncogene messenger RNAs and are therefore underexpressed in cancer. Endogenous miRNAs regulate different cellular pathways in all cell types. Therefore, they are not only key modulators in cancer cells but also in the cells constituting their microenvironments. Recently, it was shown that miRNAs are also involved in intercellular communication. Indeed, miRNAs can be transferred from one cell type to another where they regulate targeted gene expression. The primary carriers for the transfer of miRNAs from one cell to another are exosomes. Exosomes are currently considered the primary carriers for communication between the tumor and its surrounding stromal cells to support cancer progression and drive immune suppression. Exosome and miRNAs are seen by many as a hope for developing a new class of targeted therapy. This review outlines recent advances in understanding the role of oncomiRs in enhancing cancer and how they promote its aggressive characteristics and deeply discusses the role of oncomiRs in suppressing the anticancer immune response in its microenvironment. Additionally, further understanding the mechanism of oncomiR-related immune suppression will facilitate the use of miRNAs as biomarkers for impaired antitumor immune function, making them ideal immunotherapy targets.
Collapse
Affiliation(s)
- Khalid Otmani
- Experimental Hematology Laboratory, Hematology Department, Jules Bordet Institute, Brussels, Belgium
- Hematology Department, Université libre de Bruxelles, Brussels, Belgium
- *Correspondence: Khalid Otmani,
| | - Redouane Rouas
- Hematology Department, Université libre de Bruxelles, Brussels, Belgium
- Hematological Cell Therapy Unit, Hematology Department, Jules Bordet Institute, Brussels, Belgium
| | - Philippe Lewalle
- Experimental Hematology Laboratory, Hematology Department, Jules Bordet Institute, Brussels, Belgium
- Hematology Department, Université libre de Bruxelles, Brussels, Belgium
- Hematological Cell Therapy Unit, Hematology Department, Jules Bordet Institute, Brussels, Belgium
| |
Collapse
|
|
5
|
Lone SN, Bhat AA, Wani NA, Karedath T, Hashem S, Nisar S, Singh M, Bagga P, Das BC, Bedognetti D, Reddy R, Frenneaux MP, El-Rifai W, Siddiqi MA, Haris M, Macha MA. miRNAs as novel immunoregulators in cancer. Semin Cell Dev Biol 2021; 124:3-14. [PMID: 33926791 DOI: 10.1016/j.semcdb.2021.04.013] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/07/2021] [Accepted: 04/13/2021] [Indexed: 02/06/2023]
Abstract
The immune system is a well-known vital regulator of tumor growth, and one of the main hallmarks of cancer is evading the immune system. Immune system deregulation can lead to immune surveillance evasion, sustained cancer growth, proliferation, and metastasis. Tumor-mediated disruption of the immune system is accomplished by different mechanisms that involve extensive crosstalk with the immediate microenvironment, which includes endothelial cells, immune cells, and stromal cells, to create a favorable tumor niche that facilitates the development of cancer. The essential role of non-coding RNAs such as microRNAs (miRNAs) in the mechanism of cancer cell immune evasion has been highlighted in recent studies. miRNAs are small non-coding RNAs that regulate a wide range of post-transcriptional gene expression in a cell. Recent studies have focused on the function that miRNAs play in controlling the expression of target proteins linked to immune modulation. Studies show that miRNAs modulate the immune response in cancers by regulating the expression of different immune-modulatory molecules associated with immune effector cells, such as macrophages, dendritic cells, B-cells, and natural killer cells, as well as those present in tumor cells and the tumor microenvironment. This review explores the relationship between miRNAs, their altered patterns of expression in tumors, immune modulation, and the functional control of a wide range of immune cells, thereby offering detailed insights on the crosstalk of tumor-immune cells and their use as prognostic markers or therapeutic agents.
Collapse
Affiliation(s)
- Saife N Lone
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | - Ajaz A Bhat
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Nissar A Wani
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, Jammu & Kashmir, India
| | | | - Sheema Hashem
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Sabah Nisar
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar
| | - Mayank Singh
- Dr. B. R. Ambedkar Institute Rotary Cancer Hospital (BRAIRCH), AIIMS, New Delhi, India
| | - Puneet Bagga
- Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Bhudev Chandra Das
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Uttar Pradesh, India
| | - Davide Bedognetti
- Laboratory of Cancer Immunogenomics, Cancer Research Department, Sidra Medicine, Doha, Qatar; Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
| | - Ravinder Reddy
- Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
| | | | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Mushtaq A Siddiqi
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, India
| | - Mohammad Haris
- Molecular and Metabolic Imaging Laboratory, Cancer Research Department, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar.
| | - Muzafar A Macha
- Watson-Crick Centre for Molecular Medicine, Islamic University of Science and Technology, India.
| |
Collapse
|
|
6
|
Role of p53-miRNAs circuitry in immune surveillance and cancer development: A potential avenue for therapeutic intervention. Semin Cell Dev Biol 2021; 124:15-25. [PMID: 33875349 DOI: 10.1016/j.semcdb.2021.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 03/07/2021] [Accepted: 04/02/2021] [Indexed: 12/16/2022]
Abstract
The genome's guardian, p53, is a master regulatory transcription factor that occupies sequence-specific response elements in many genes and modulates their expression. The target genes transcribe both coding RNA and non-coding RNA involved in regulating several biological processes such as cell division, differentiation, and cell death. Besides, p53 also regulates tumor immunology via regulating the molecules related to the immune response either directly or via regulating other molecules, including microRNAs (miRNAs). At the post-transcriptional level, the regulations of genes by miRNAs have been an emerging mechanism. Interestingly, p53 and various miRNAs cross-talk at different regulation levels. The cross-talk between p53 and miRNAs creates loops, turns, and networks that can influence cell metabolism, cell fate, cellular homeostasis, and tumor formation. Further, p53-miRNAs circuit has also been insinuated in the regulation of immune surveillance machinery. There are several examples of p53-miRNAs circuitry where p53 regulates immunomodulatory miRNA expression, such as miR-34a and miR-17-92. Similarly, a reverse process occurs in which miRNAs such as miR-125b and miR-let-7 regulate the expression of p53. Thus, the p53-miRNAs circuitry connects the immunomodulatory pathways and may shift the pro-inflammatory balance towards the pro-tumorigenic condition. In this review, we discuss the influence of p53-miRNAs circuitry in modulating the immune response in cancer development. We assume that thorough studies on the p53-miRNAs circuitry in various cancers may prove useful in developing effective new cancer therapeutics for successfully combating this disease.
Collapse
|
|
7
|
Mondal P, Kaur B, Natesh J, Meeran SM. The emerging role of miRNA in the perturbation of tumor immune microenvironment in chemoresistance: Therapeutic implications. Semin Cell Dev Biol 2021; 124:99-113. [PMID: 33865701 DOI: 10.1016/j.semcdb.2021.04.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/16/2021] [Accepted: 04/02/2021] [Indexed: 02/07/2023]
Abstract
Chemoresistance is a major hindrance in cancer chemotherapies, a leading cause of tumor recurrence and cancer-related deaths. Cancer cells develop numerous strategies to elude immune attacks and are regulated by immunological factors. Cancer cells can alter the expression of several immune modulators to upregulate the activities of immune checkpoint pathways. Targeting the immune checkpoint inhibitors is a part of the cancer immunotherapy altered during carcinogenesis. These immune modulators have the capability to reprogram the tumor microenvironment, thereby change the efficacy of chemotherapeutics. In general, the sensitivity of drugs is reduced in the immunosuppressive tumor microenvironment, resulting in chemoresistance and tumor relapse. The regulation of microRNAs (miRNAs) is well established in cancer initiation, progression, and therapy. Intriguingly, miRNA affects cancer immune surveillance and immune response by targeting immune checkpoint inhibitors in the tumor microenvironment. miRNAs alter the gene expression at the post-transcriptional level, which modulates both innate and adaptive immune systems. Alteration of tumor immune microenvironment influences drug sensitivity towards cancer cells. Besides, the expression profile of immune-modulatory miRNAs can be used as a potential biomarker to predict the response and clinical outcomes in cancer immunotherapy and chemotherapy. Recent evidences have revealed that cancer-derived immune-modulatory miRNAs might be promising targets to counteract cancer immune escape, thereby increasing drug efficacy. In this review, we have compiled the role of miRNAs in overcoming the chemoresistance by modulating tumor microenvironment and discussed their preclinical and clinical implications.
Collapse
Affiliation(s)
- Priya Mondal
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Bhavjot Kaur
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India
| | - Jagadish Natesh
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Syed Musthapa Meeran
- Department of Biochemistry, CSIR-Central Food Technological Research Institute, Mysore 570020, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| |
Collapse
|
|
8
|
DHA Abolishes the Detrimental Effect of Docetaxel on Downregulation of the MICA via Decreasing the Expression Level of MicroRNA-20a in Gastric Cancer. J Gastrointest Cancer 2021; 51:545-551. [PMID: 31368060 DOI: 10.1007/s12029-019-00280-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND MHC class I chain-related protein A (MICA) is a membrane glycoprotein expressed abnormally on some malignant cells including gastric cancer (GC) cell and elicits anti-tumor immune responses. Downregulation of MICA expression could lead to immune-evasion of cancer cells. OBJECTIVE(S) In this study, we aimed to investigate the effect of docosahexaenoic acid (DHA) and docetaxel alone or in combination on the expression level of MICA and its regulating microRNA (miRNA), miR-20a in MKN45 GC cell line. METHOD(S) MKN45 GC cell line was cultured and MTT assay was performed to determine IC50 of docetaxel. Cells were treated by 18.5 μM docetaxel and 100 μM DHA. After that, RNA extraction and cDNA synthesis were done and the expression level of MICA and miR-20a were determined by quantitative real-time PCR for both treated and untreated cell lines. RESULTS Our findings showed less downregulation of the expression level of MICA by the combination of docetaxel/DHA (5.34-fold) compared with docetaxel (45.45-fold) and DHA (55.55-fold). Consistently, combination therapy led to the more downregulation of the expression level of the miR-20a (5.20-fold) in comparison to docetaxel (2.38-fold) and DHA (1.60-fold). CONCLUSION(S) As an unwanted effect of docetaxel therapy in GC, downregulation of MICA expression could lead to weak anti-tumor immune responses. By increasing the expression level of MICA, combination therapy of docetaxel with DHA would be useful to overcome this side effect.
Collapse
|
|
9
|
Sekiba K, Otsuka M, Seimiya T, Tanaka E, Funato K, Miyakawa Y, Koike K. The fatty-acid amide hydrolase inhibitor URB597 inhibits MICA/B shedding. Sci Rep 2020; 10:15556. [PMID: 32968163 PMCID: PMC7512021 DOI: 10.1038/s41598-020-72688-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 08/31/2020] [Indexed: 01/21/2023] Open
Abstract
MICA/B proteins are expressed on the surface of various types of stressed cells, including cancer cells. Cytotoxic lymphocytes expressing natural killer group 2D (NKG2D) receptor recognize MICA/B and eliminate the cells. However, cancer cells evade such immune recognition by inducing proteolytic shedding of MICA/B proteins. Therefore, preventing the shedding of MICA/B proteins could enhance antitumor immunity. Here, by screening a protease inhibitor library, we found that the fatty-acid amide hydrolase (FAAH) inhibitor, URB597, suppresses the shedding of MICA/B. URB597 significantly reduced the soluble MICA level in culture medium and increased the MICA level on the surface of cancer cells. The effect was indirect, being mediated by increased expression of tissue inhibitor of metalloproteinases 3 (TIMP3). Knockdown of TIMP3 expression reversed the effect of URB597, confirming that TIMP3 is required for the MICA shedding inhibition by URB597. In contrast, FAAH overexpression reduced TIMP3 expression and the cell-surface MICA level and increased the soluble MICA level. These results suggest that inhibition of FAAH could prevent human cancer cell evasion of immune-mediated clearance.
Collapse
Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
- Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan
| | - Eri Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kazuyoshi Funato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Yu Miyakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
| |
Collapse
|
|
10
|
Cantoni C, Wurzer H, Thomas C, Vitale M. Escape of tumor cells from the NK cell cytotoxic activity. J Leukoc Biol 2020; 108:1339-1360. [PMID: 32930468 DOI: 10.1002/jlb.2mr0820-652r] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/11/2020] [Accepted: 08/13/2020] [Indexed: 12/15/2022] Open
Abstract
In recent years, NK cells, initially identified as potent cytotoxic effector cells, have revealed an unexpected complexity, both at phenotypic and functional levels. The discovery of different NK cell subsets, characterized by distinct gene expression and phenotypes, was combined with the characterization of the diverse functions NK cells can exert, not only as circulating cells, but also as cells localized or recruited in lymphoid organs and in multiple tissues. Besides the elimination of tumor and virus-infected cells, these functions include the production of cytokines and chemokines, the regulation of innate and adaptive immune cells, the influence on tissue homeostasis. In addition, NK cells display a remarkable functional plasticity, being able to adapt to the environment and to develop a kind of memory. Nevertheless, the powerful cytotoxic activity of NK cells remains one of their most relevant properties, particularly in the antitumor response. In this review, the process of tumor cell recognition and killing mediated by NK cells, starting from the generation of cytolytic granules and recognition of target cell, to the establishment of the NK cell immunological synapse, the release of cytotoxic molecules, and consequent tumor cell death is described. Next, the review focuses on the heterogeneous mechanisms, either intrinsic to tumors or induced by the tumor microenvironment, by which cancer cells can escape the NK cell-mediated attack.
Collapse
Affiliation(s)
- Claudia Cantoni
- Department of Experimental Medicine and Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.,Laboratory of Clinical and Experimental Immunology, Integrated Department of Services and Laboratories, IRCCS Istituto G. Gaslini, Genoa, Italy
| | - Hannah Wurzer
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg.,Faculty of Science, Technology and Medicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg
| | - Clément Thomas
- Cytoskeleton and Cancer Progression, Department of Oncology, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Massimo Vitale
- UO Immunologia, IRCCS Ospedale Policlinico San Martino Genova, Genoa, Italy
| |
Collapse
|
|
11
|
Ochi M, Otsuka M, Maruyama R, Koike K. HBx increases EGFR expression by inhibiting miR129-5p function. Biochem Biophys Res Commun 2020; 529:198-203. [PMID: 32703411 DOI: 10.1016/j.bbrc.2020.06.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 06/04/2020] [Indexed: 12/29/2022]
Abstract
Despite the efficient suppression of hepatitis B virus (HBV) replication by nucelos(t)ide analogs, HBV RNA expression usually continues even during nucleots(t)ide analog therapy because episomal covalently closed circular DNA (ccDNA), which is the template for HBV RNA transcription, cannot be eliminated. Here, we found that the common sequences of all HBV RNAs and that encoding the X protein (HBx) have similarities with the sequences of a host cellular microRNA (miRNA), miR129-5p. HBx inhibits miR129-5p function, resulting in increased expression of ZBTB20, a target gene of miR129-5p. ZBTB20 activates transcription and increases cell-surface epidermal growth factor receptor (EGFR) levels, promoting the cell growth rate, and this effect was reversed through ZBTB20 knockdown. mir129-5p levels in Ago2-containing complexes were reduced by expression of HBx, suggesting that the viral RNA sequestered miR129-5p from Ago2-containing complexes. These results indicate the possibility that HBV RNA may maintain pathogenicity even through nucleos(t)ide analog therapy.
Collapse
Affiliation(s)
- Masanori Ochi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| | - Reo Maruyama
- Project for Cancer Epigenomics, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
| |
Collapse
|
|
12
|
Chitnis NS, Shieh M, Monos D. Regulatory noncoding RNAs and the major histocompatibility complex. Hum Immunol 2020; 82:532-540. [PMID: 32636038 DOI: 10.1016/j.humimm.2020.06.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/21/2020] [Accepted: 06/09/2020] [Indexed: 12/15/2022]
Abstract
The Major Histocompatibility Complex (MHC) is a 4 Mbp genomic region located on the short arm of chromosome 6. The MHC region contains many key immune-related genes such as Human Leukocyte Antigens (HLAs). There has been a growing realization that, apart from MHC encoded proteins, RNAs derived from noncoding regions of the MHC-specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs)-play a significant role in cellular regulation. Furthermore, regulatory noncoding RNAs (ncRNAs) derived from other parts of the genome fine-tune the expression of many immune-related MHC proteins. Although the field of ncRNAs of the MHC is a research area that is still in its infancy, ncRNA regulation of MHC genes has already been shown to be vital for immune function, healthy pregnancy and cellular homeostasis. Dysregulation of this intricate network of ncRNAs can lead to serious perturbations in homeostasis and subsequent disease.
Collapse
Affiliation(s)
- Nilesh Sunil Chitnis
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Mengkai Shieh
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Dimitri Monos
- Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| |
Collapse
|
|
13
|
microRNAs in the Antitumor Immune Response and in Bone Metastasis of Breast Cancer: From Biological Mechanisms to Therapeutics. Int J Mol Sci 2020; 21:ijms21082805. [PMID: 32316552 PMCID: PMC7216039 DOI: 10.3390/ijms21082805] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 04/03/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is the most common type of cancer in women, and the occurrence of metastasis drastically worsens the prognosis and reduces overall survival. Understanding the biological mechanisms that regulate the transformation of malignant cells, the consequent metastatic transformation, and the immune surveillance in the tumor progression would contribute to the development of more effective and targeted treatments. In this context, microRNAs (miRNAs) have proven to be key regulators of the tumor-immune cells crosstalk for the hijack of the immunosurveillance to promote tumor cells immune escape and cancer progression, as well as modulators of the metastasis formation process, ranging from the preparation of the metastatic site to the transformation into the migrating phenotype of tumor cells. In particular, their deregulated expression has been linked to the aberrant expression of oncogenes and tumor suppressor genes to promote tumorigenesis. This review aims at summarizing the role and functions of miRNAs involved in antitumor immune response and in the metastasis formation process in breast cancer. Additionally, miRNAs are promising targets for gene therapy as their modulation has the potential to support or inhibit specific mechanisms to negatively affect tumorigenesis. With this perspective, the most recent strategies developed for miRNA-based therapeutics are illustrated.
Collapse
|
|
14
|
Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches. Cancers (Basel) 2020; 12:cancers12040926. [PMID: 32283827 PMCID: PMC7226319 DOI: 10.3390/cancers12040926] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/03/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success. Natural killer (NK) cells are an essential component of innate immunity against cancer and changes in phenotype and function have been described in patients with HCC, who also show perturbations of NK activating receptor/ligand axes. Here we discuss the current status of NK cell treatment of HCC on the basis of existing evidence and ongoing clinical trials on adoptive transfer of autologous or allogeneic NK cells ex vivo or after activation with cytokines such as IL-15 and use of antibodies to target cell-expressed molecules to promote antibody-dependent cellular cytotoxicity (ADCC). To this end, bi-, tri- and tetra-specific killer cell engagers are being devised to improve NK cell recognition of tumor cells, circumventing tumor immune escape and efficiently targeting NK cells to tumors. Moreover, the exciting technique of chimeric antigen receptor (CAR)-engineered NK cells offers unique opportunities to create CAR-NK with multiple specificities along the experience gained with CAR-T cells with potentially less adverse effects.
Collapse
|
|
15
|
Yi M, Xu L, Jiao Y, Luo S, Li A, Wu K. The role of cancer-derived microRNAs in cancer immune escape. J Hematol Oncol 2020; 13:25. [PMID: 32222150 PMCID: PMC7103070 DOI: 10.1186/s13045-020-00848-8] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/14/2020] [Indexed: 12/18/2022] Open
Abstract
During malignant transformation, accumulated somatic mutations endow cancer cells with increased invasiveness and immunogenicity. Under selective pressure, these highly immunogenic cancer cells develop multiple strategies to evade immune attack. It has been well established that cancer cells could downregulate the expression of major histocompatibility complex, acquire alterations in interferon pathway, and upregulate the activities of immune checkpoint pathways. Besides, cancer cells secret numerous cytokines, exosomes, and microvesicles to regulate the functions and abundances of components in the tumor microenvironment including immune effector cells and professional antigen presentation cells. As the vital determinant of post-transcriptional regulation, microRNAs (miRNAs) not only participate in cancer initiation and progression but also regulate anti-cancer immune response. For instance, some miRNAs affect cancer immune surveillance and immune escape by interfering the expression of immune attack-associated molecules. A growing body of evidence indicated that cancer-derived immune modulatory miRNAs might be promising targets to counteract cancer immune escape. In this review, we summarized the role of some miRNAs in cancer immune escape and discussed their potential clinical application as treatment targets.
Collapse
Affiliation(s)
- Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Linping Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Ying Jiao
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
| | - Suxia Luo
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Anping Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030 China
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008 China
| |
Collapse
|
|
16
|
Pesce S, Greppi M, Ferretti E, Obino V, Carlomagno S, Rutigliani M, Thoren FB, Sivori S, Castagnola P, Candiani S, Marcenaro E. miRNAs in NK Cell-Based Immune Responses and Cancer Immunotherapy. Front Cell Dev Biol 2020; 8:119. [PMID: 32161759 PMCID: PMC7053181 DOI: 10.3389/fcell.2020.00119] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/11/2020] [Indexed: 12/16/2022] Open
Abstract
The incidence of certain forms of tumors has increased progressively in recent years and is expected to continue growing as life expectancy continues to increase. Tumor-infiltrating NK cells may contribute to develop an anti-tumor response. Optimized combinations of different cancer therapies, including NK cell-based approaches for targeting tumor cells, have the potential to open new avenues in cancer immunotherapy. Functional inhibitory receptors on NK cells are needed to prevent their attack on healthy cells. Nevertheless, disruption of inhibitory receptors function on NK cells increases the cytotoxic capacity of NK cells against cancer cells. MicroRNAs (miRNAs) are small non-coding RNA molecules that target mRNA and thus regulate the expression of genes involved in the development, maturation, and effector functions of NK cells. Therapeutic strategies that target the regulatory effects of miRNAs have the potential to improve the efficiency of cancer immunotherapy. Interestingly, emerging evidence points out that some miRNAs can, directly and indirectly, control the surface expression of immune checkpoints on NK cells or that of their ligands on tumor cells. This suggests a possible use of miRNAs in the context of anti-tumor therapy. This review provides the current overview of the connections between miRNAs and regulation of NK cell functions and discusses the potential of these miRNAs as innovative biomarkers/targets for cancer immunotherapy.
Collapse
Affiliation(s)
- Silvia Pesce
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Marco Greppi
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Elisa Ferretti
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Valentina Obino
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - Simona Carlomagno
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Mariangela Rutigliani
- Histological and Anatomical Pathology Unit, Department of Laboratory and Service, E.O. Galliera Hospital, Genova, Italy
| | - Fredrik B Thoren
- Tumor Immunology Laboratory (TIMM) Laboratory at Sahlgrenska Cancer Center, Department of Infectious Diseases, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Simona Sivori
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | | | - Simona Candiani
- Department of Earth Science, Environment and Life (DISTAV), University of Genoa, Genoa, Italy
| | - Emanuela Marcenaro
- Department of Experimental Medicine, University of Genoa, Genoa, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| |
Collapse
|
|
17
|
Omar HA, El‐Serafi AT, Hersi F, Arafa EA, Zaher DM, Madkour M, Arab HH, Tolba MF. Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment. FEBS J 2019; 286:3540-3557. [DOI: 10.1111/febs.15000] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Revised: 05/29/2019] [Accepted: 07/12/2019] [Indexed: 12/15/2022]
Affiliation(s)
- Hany A. Omar
- Sharjah Institute for Medical Research University of Sharjah UAE
- Department of Pharmacology, Faculty of Pharmacy Beni‐Suef University Egypt
| | - Ahmed T. El‐Serafi
- Sharjah Institute for Medical Research University of Sharjah UAE
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine Suez Canal University Ismailia Egypt
| | - Fatema Hersi
- Sharjah Institute for Medical Research University of Sharjah UAE
| | - El‐Shaimaa A. Arafa
- Department of Clinical Sciences, College of Pharmacy and Health Sciences Ajman University UAE
| | - Dana M. Zaher
- Sharjah Institute for Medical Research University of Sharjah UAE
| | - Mohamed Madkour
- Sharjah Institute for Medical Research University of Sharjah UAE
| | - Hany H. Arab
- Department of Biochemistry, Faculty of Pharmacy Cairo University Egypt
- Biochemistry Division and GTMR Unit, Department of Pharmacology and Toxicology, Faculty of Pharmacy Taif University Saudi Arabia
| | - Mai F. Tolba
- Department of Pharmacology and Toxicology, Faculty of Pharmacy Ain Shams University Cairo Egypt
- Biology Department, School of Sciences and Engineering The American University in Cairo New Cairo Egypt
| |
Collapse
|
|
18
|
Trinh TL, Kandell WM, Donatelli SS, Tu N, Tejera MM, Gilvary DL, Eksioglu EA, Burnette A, Adams WA, Liu J, Teer JK, Djeu JY, Coppola D, Wei S. Immune evasion by TGFβ-induced miR-183 repression of MICA/B expression in human lung tumor cells. Oncoimmunology 2019; 8:e1557372. [PMID: 30906652 PMCID: PMC6422376 DOI: 10.1080/2162402x.2018.1557372] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 11/07/2018] [Accepted: 12/01/2018] [Indexed: 01/02/2023] Open
Abstract
Immune escape is a hallmark of cancer. In human lung cancer, we have identified a unique microRNA (miR)-based pathway employed by tumor cells to repress detection by immune cells via the NKG2D-MICA/B receptor-ligand system. MICA/B is readily induced by cell transformation and serves as a danger signal and ligand to alert NK and activated CD8+ T cells. However, immunohistochemical analysis indicated that human lung adenocarcinoma and squamous cell carcinoma specimens express little MICA/B while high levels of miR-183 were detected in both tumor types in a TCGA database. Human lung tumor cell lines confirmed the reverse relationship in expression of MICA/B and miR-183. Importantly, a miR-183 binding site was identified on the 3'untranslated region (UTR) of both MICA and MICB, suggesting its role in MICA/B regulation. Luciferase reporter constructs bearing the 3'UTR of MICA or MICB in 293 cells supported the function of miR-183 in repressing MICA/B expression. Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B. Abundant miR-183 expression in tumor cells was traced to transforming growth factor-beta (TGFβ), as evidenced by antisense TGFβ transfection into H1355 or H1299 tumor cells which subsequently lost miR-183 expression accompanied by MICA/B upregulation. Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8+ T cells that express high levels of NKG2D. Thus, high miR-183 triggered by TGFβ expressed in lung tumor cells can target MICA/B expression to circumvent detection by NKG2D on immune cells.
Collapse
Affiliation(s)
- Thu Le Trinh
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Wendy M Kandell
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
| | | | - Nhan Tu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Melba M Tejera
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Erika A Eksioglu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Alexis Burnette
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - William A Adams
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jinhong Liu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | - Jamie K Teer
- Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Julie Y Djeu
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Sheng Wei
- Departments of Immunology, Moffitt Cancer Center, Tampa, FL, USA
| |
Collapse
|
|
19
|
Wong TS, Chen S, Zhang MJ, Chan JYW, Gao W. Epstein-Barr virus-encoded microRNA BART7 downregulates major histocompatibility complex class I chain-related peptide A and reduces the cytotoxicity of natural killer cells to nasopharyngeal carcinoma. Oncol Lett 2018; 16:2887-2892. [PMID: 30127876 PMCID: PMC6096257 DOI: 10.3892/ol.2018.9041] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Accepted: 04/26/2018] [Indexed: 01/10/2023] Open
Abstract
Evasion from natural killer (NK) cell surveillance enables cancer to proliferate and spread at the early stages. NK cells mediate specific cytolysis by activation of the triggering receptors on their cell surface, of which the communication between natural killer group 2, member D (NKG2D) and major histocompatibility complex class I chain-related peptide A (MICA) is a key regulatory axis. It has been indicated that cancer cells can reduce the surface expression of MICA, which thereby reduces the cytotoxicity of NK cells. In nasopharyngeal carcinoma (NPC), however, the underlying mechanism remains unclear. The present study indicated that MICA expression in NPC was regulated by TGFβ1. Furthermore, the human MICA gene was demonstrated to contain the c-Myc binding site in the promoter region. Notably, the results suggested that TGFβ1 upregulated MICA expression by promoting c-Myc expression. Additionally, the findings demosntrated that TGFβ1 expression in NPC was negatively controlled by Epstein-Barr virus-encoded microRNA BART7 (ebv-miR-BART7). In ebv-miR-BART7-expressing NPC, the TGFβ1/c-Myc/MICA regulatory axis was significantly inhibited. Notably, functional analysis indicated that NPC cells expressing ebv-miR-BART7 were less sensitive to the cytolysis mediated by NK cells. In conclusion, the present results revealed that ebv-miR-BART7-expressing NPC may impair NK cells recognition and activity, which suggests that targeting ebv-miR-BART7 may be a useful therapeutic strategy in NPC immunotherapy.
Collapse
Affiliation(s)
- Thian-Sze Wong
- Department of Surgery, The University of Hong Kong, Hong Kong SAR, P.R. China
| | - Siqi Chen
- Department of Surgery, The University of Hong Kong, Hong Kong SAR, P.R. China
| | - Min-Juan Zhang
- Department of Surgery, The University of Hong Kong, Hong Kong SAR, P.R. China
| | - Jimmy Yu-Wai Chan
- Department of Surgery, The University of Hong Kong, Hong Kong SAR, P.R. China
| | - Wei Gao
- Department of Surgery, The University of Hong Kong, Hong Kong SAR, P.R. China
| |
Collapse
|
|
20
|
Sárközy M, Kahán Z, Csont T. A myriad of roles of miR-25 in health and disease. Oncotarget 2018; 9:21580-21612. [PMID: 29765562 PMCID: PMC5940376 DOI: 10.18632/oncotarget.24662] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 01/30/2018] [Indexed: 02/06/2023] Open
Abstract
Small non-coding RNAs including microRNAs (miRNAs) have been recently recognized as important regulators of gene expression. MicroRNAs play myriads of roles in physiological processes as well as in the pathogenesis of a number of diseases by translational repression or mRNA destabilization of numerous target genes. The miR-106b-25 cluster is highly conserved in vertebrates and consists of three members including miR-106b, miR-93 and miR-25. MiR-106b and miR-93 share the same seed sequences; however, miR-25 has only a similar seed sequence resulting in different predicted target mRNAs. In this review, we specifically focus on the role of miR-25 in healthy and diseased conditions. Many of miR-25 target mRNAs are involved in biological processes such as cell proliferation, differentiation, and migration, apoptosis, oxidative stress, inflammation, calcium handling, etc. Therefore, it is no surprise that miR-25 has been reported as a key regulator of common cancerous and non-cancerous diseases. MiR-25 plays an important role in the pathogenesis of acute myocardial infarction, left ventricular hypertrophy, heart failure, diabetes mellitus, diabetic nephropathy, tubulointerstitial nephropathy, asthma bronchiale, cerebral ischemia/reperfusion injury, neurodegenerative diseases, schizophrenia, multiple sclerosis, etc. MiR-25 is also a well-described oncogenic miRNA playing a crucial role in the development of many tumor types including brain tumors, lung, breast, ovarian, prostate, thyroid, oesophageal, gastric, colorectal, hepatocellular cancers, etc. In this review, our aim is to discuss the translational therapeutic role of miR-25 in common diseased conditions based on relevant basic research and clinical studies.
Collapse
Affiliation(s)
- Márta Sárközy
- Department of Biochemistry, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary
| | - Zsuzsanna Kahán
- Department of Oncotherapy, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary
| | - Tamás Csont
- Department of Biochemistry, Faculty of Medicine, University of Szeged, H-6720 Szeged, Hungary
| |
Collapse
|
|
21
|
Yang X, Kuang S, Wang L, Wei Y. MHC class I chain-related A: Polymorphism, regulation and therapeutic value in cancer. Biomed Pharmacother 2018; 103:111-117. [PMID: 29635123 DOI: 10.1016/j.biopha.2018.03.177] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/27/2018] [Accepted: 03/28/2018] [Indexed: 12/20/2022] Open
Abstract
MICA and MICB are stress-induced molecules recognized by NKG2D, one of major activation receptors of natural killer (NK) cells. Upon binding to NKG2D, NKG2D-mediated cytolytic immune response of immune effector cells will be activated against virally infected and tumor cells expressing MICA. In the early oncogenic development, membrane-bound MICA serves as a key signal to recruit anti-tumor immune effectors. Nevertheless, both MICA polymorphic features and its dysregulated expression in evolving tumors have resulted in tumor evasion in various cancer types. Therefore, in order to reconstitute tumor immunosurveilance, it is of great significance that we understand MICA genetics, polymorphisms, mechanisms of MICA-associated tumor escape and molecular/cellular modulation of MICA. In this review, the MICA-associated co-expression networks involving microRNAs (miRNAs) and novel candidate long non-coding RNAs (lncRNAs) were also discussed. Given the current importance in the study of MICA gene, this review paper focuses on the role of MICA in different cancer types, and strategies that we manipulate MICA regulation against tumor proliferation.
Collapse
Affiliation(s)
- Xi Yang
- Department of Biological Sciences, Clemson University, USA
| | - Shuzhen Kuang
- Department of Biological Sciences, Clemson University, USA
| | - Liangjiang Wang
- Department of Genetics and Biochemistry, Clemson University, USA.
| | - Yanzhang Wei
- Department of Biological Sciences, Clemson University, USA.
| |
Collapse
|
|
22
|
Dhar P, Wu JD. NKG2D and its ligands in cancer. Curr Opin Immunol 2018; 51:55-61. [PMID: 29525346 PMCID: PMC6145810 DOI: 10.1016/j.coi.2018.02.004] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 02/02/2018] [Accepted: 02/23/2018] [Indexed: 01/12/2023]
Abstract
NKG2D is an activating immune receptor expressed by NK and effector T cells. Induced expression of NKG2D ligand on tumor cell surface during oncogenic insults renders cancer cells susceptible to immune destruction. In advanced human cancers, tumor cells shed NKG2D ligand to produce an immune soluble form as a means of immune evasion. Soluble NKG2D ligands have been associated with poor clinical prognosis in cancer patients. Harnessing NKG2D pathway is considered a viable avenue in cancer immunotherapy over recent years. In this review, we will discuss the progress and perspectives.
Collapse
Affiliation(s)
- Payal Dhar
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago IL60611, United States; Driskill Graduate Program in Life Sciences, Feinberg School of Medicine, Chicago, Northwestern University, Chicago IL60611, United States
| | - Jennifer D Wu
- Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago IL60611, United States; Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago IL60611, United States; Robert Lurie Comprehensive Cancer Center, Northwestern University, Chicago IL60611, United States.
| |
Collapse
|
|
23
|
Yao X, Cui X, Wu X, Xu P, Zhu W, Chen X, Zhao T. Tumor suppressive role of miR-1224-5p in keloid proliferation, apoptosis and invasion via the TGF-β1/Smad3 signaling pathway. Biochem Biophys Res Commun 2018; 495:713-720. [DOI: 10.1016/j.bbrc.2017.10.070] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 10/14/2017] [Indexed: 01/10/2023]
|
|
24
|
Zhang Z, Che X, Yang N, Bai Z, Wu Y, Zhao L, Pei H. miR-135b-5p Promotes migration, invasion and EMT of pancreatic cancer cells by targeting NR3C2. Biomed Pharmacother 2017; 96:1341-1348. [PMID: 29196101 DOI: 10.1016/j.biopha.2017.11.074] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 11/13/2017] [Accepted: 11/13/2017] [Indexed: 12/27/2022] Open
Abstract
The exact mechanisms of metastasis for pancreatic cancer remain to be uncovered. This study aimed to elucidate the potential functional mechanism of miR-135b-5p in migration, invasion and epithelial-to-mesenchymal transition (EMT) of pancreatic cancer cells. By real-time PCR and analysis of GEO database, we determined the up-regulated expression of miR-135b-5p in pancreatic cancer tissues and cell lines. Clinically, highly expressed miR-135b-5p was closely related to advanced TNM stage, more lymph node metastasis, more distant metastasis and worse overall survival (OS) and disease-free survival (DFS). Functionally, Transwell assays indicated that miR-135b-5p was a promoter for migration and invasion of pancreatic cancer cells. Additionally, immunohistochemistry staining and Western blot showed that highly expressed miR-135b-5p accelerated EMT process of pancreatic cancer cells. Furthermore, a series of experiments and rescue experiments revealed that Nuclear Receptor Subfamily 3 Group C Member 2 (NR3C2) was the target of miR-135b-5p in pancreatic cancer cells, mediating the promotion effects of miR-135b-5p on the tumor cells migration, invasion and EMT. In conclusion, miR-135b-5p, maybe a novel therapeutic target for pancreatic cancer, promoted migration, invasion and EMT of pancreatic cancer cells by targeting NR3C2.
Collapse
Affiliation(s)
- Zhengliang Zhang
- Department of Emergency, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Xiangming Che
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Ni Yang
- Department of Emergency, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Zhenghai Bai
- Department of Emergency, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Yuan Wu
- Department of Emergency, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Li Zhao
- Department of Emergency, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China
| | - Honghong Pei
- Department of Emergency, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710004, China.
| |
Collapse
|
|
25
|
Eichmüller SB, Osen W, Mandelboim O, Seliger B. Immune Modulatory microRNAs Involved in Tumor Attack and Tumor Immune Escape. J Natl Cancer Inst 2017; 109:3105955. [PMID: 28383653 DOI: 10.1093/jnci/djx034] [Citation(s) in RCA: 110] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Accepted: 02/13/2017] [Indexed: 12/17/2022] Open
Abstract
Current therapies against cancer utilize the patient's immune system for tumor eradication. However, tumor cells can evade immune surveillance of CD8+ T and/or natural killer (NK) cells by various strategies. These include the aberrant expression of human leukocyte antigen (HLA) class I antigens, co-inhibitory or costimulatory molecules, and components of the interferon (IFN) signal transduction pathway. In addition, alterations of the tumor microenvironment could interfere with efficient antitumor immune responses by downregulating or inhibiting the frequency and/or functional activity of immune effector cells and professional antigen-presenting cells. Recently, microRNAs (miRNAs) have been identified as major players in the post-transcriptional regulation of gene expression, thereby controlling many physiological and also pathophysiological processes including neoplastic transformation. Indeed, the cellular miRNA expression pattern is frequently altered in many tumors of distinct origin, demonstrating the tumor suppressive or oncogenic potential of miRNAs. Furthermore, there is increasing evidence that miRNAs could also influence antitumor immune responses by affecting the expression of immune modulatory molecules in tumor and immune cells. Apart from their important role in tumor immune escape and altered tumor-host interaction, immune modulatory miRNAs often exert neoplastic properties, thus representing promising targets for future combined immunotherapy approaches. This review focuses on the characterization of miRNAs involved in the regulation of immune surveillance or immune escape of tumors and their potential use as diagnostic and prognostic biomarkers or as therapeutic targets.
Collapse
Affiliation(s)
- Stefan B Eichmüller
- GMP and T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel; Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
| | - Wolfram Osen
- GMP and T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel; Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
| | - Ofer Mandelboim
- GMP and T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel; Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
| | - Barbara Seliger
- GMP and T Cell Therapy Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Kerem, Jerusalem, Israel; Institute of Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany
| |
Collapse
|
|
26
|
Sinha PB, Tesfaye D, Rings F, Hossien M, Hoelker M, Held E, Neuhoff C, Tholen E, Schellander K, Salilew-Wondim D. MicroRNA-130b is involved in bovine granulosa and cumulus cells function, oocyte maturation and blastocyst formation. J Ovarian Res 2017. [PMID: 28629378 PMCID: PMC5477299 DOI: 10.1186/s13048-017-0336-1] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background Oocyte maturation and preimplantation embryo development are controlled by array of genes that are post-transcriptionally regulated by microRNAs. With respect to this, previously, we identified altered expression of microRNA-130b (miR-130b) during oocyte maturation. Here, we aimed to investigate the role of miR-130b in bovine granulosa and cumulus cell function, oocyte maturation and preimplantation embryo development using gain- and loss-of- function approach. Methods For this study, the granulosa cells, cumulus cells and the oocytes were collected from ovaries obtained from slaughterhouse. The genes targeted by miR-130b were identified using dual-luciferase reporter assay. The role of miR-130b in granulosa and cumulus cell function was investigated by increasing and inhibiting its expression in in vitro cultured cells using miR-130b precursor and inhibitor, respectively while the role of miR-130b on oocyte development, immature oocytes were microinjected with miR-130b precursor and inhibitor and the polar body extrusion, the proportion of oocytes reaching to metaphase II stage and the mitochondrial were determined in each oocyte group 22 h after microinjection. Moreover, to investigate the role of miR-130b during preimplantation embryo development, zygote stage embryos were microinjected with miR-130b precursor or inhibitor and the cleavage rate, morula and blastocyst formation was analyzed in embryos derived from each zygote group after in vitro culture. Results The luciferase assay showed that SMAD5 and MSK1 genes were identified as the direct targets of miR-130b. Overexpression of miR-130b increased the granulosa and cumulus cell proliferation, while inhibition showed the opposite phenotype. Apart from these, modulation of miR-130b altered the lactate production and cholesterol biosynthesis in cumulus cells. Furthermore, inhibition of miR-130b expression during oocyte in vitro maturation reduced the first polar body extrusion, the proportion of oocytes reaching to metaphase II stage and the mitochondrial activity, while inhibition of miR-130b during preimplantation embryo development significantly reduced morula and blastocyst formation. Conclusion This study demonstrated that in vitro functional modulation of miR-130b affected granulosa and cumulus cell proliferation and survival, oocyte maturation, morula and blastocyst formation suggesting that miR-130b is involved in bovine oocyte maturation and preimplantation embryo development. Electronic supplementary material The online version of this article (doi:10.1186/s13048-017-0336-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Pritam Bala Sinha
- Present address: Department of Biotechnology, Engineering and Applied Sciences, Amity University Ranchi, Ranchi, Jharkhand, 834002, India
| | - Dawit Tesfaye
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany.,Center of Integrated Dairy Research, University of Bonn, Meckenheimer Allee 172, 53115, Bonn, Germany
| | - Franca Rings
- Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany
| | - Munir Hossien
- Present address: Department of Animal Breeding and Genetics, Bangladesh Agricultural University, Mymensingh, -2202, Bangladesh
| | - Michael Hoelker
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany.,Center of Integrated Dairy Research, University of Bonn, Meckenheimer Allee 172, 53115, Bonn, Germany
| | - Eva Held
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany
| | - Christaine Neuhoff
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany
| | - Ernst Tholen
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany
| | - Karl Schellander
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.,Teaching and Research Station Frankenforst, Faculty of Agriculture, University of Bonn, Frankenforsterweg 4, 53639, Königswinter, Germany.,Center of Integrated Dairy Research, University of Bonn, Meckenheimer Allee 172, 53115, Bonn, Germany
| | - Dessie Salilew-Wondim
- Institute of Animal Science, Department of Animal Breeding and Husbandry, University of Bonn, Endenicher Allee 15, 53115, Bonn, Germany.
| |
Collapse
|
|
27
|
Sekiba K, Yamagami M, Otsuka M, Suzuki T, Kishikawa T, Ishibashi R, Ohno M, Sato M, Koike K. Transcriptional activation of the MICA gene with an engineered CRISPR-Cas9 system. Biochem Biophys Res Commun 2017; 486:521-525. [PMID: 28322797 DOI: 10.1016/j.bbrc.2017.03.076] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 03/16/2017] [Indexed: 01/03/2023]
Abstract
Major histocompatibility complex class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. Because immune cells, such as natural killer (NK) cells, recognize virally infected or transformed cells and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells, MICA expression levels are associated with NK cell-mediated immunity. Here, we report that an engineered clustered regularly interspaced short palindromic repeats-Cas9-related complex targeting MICA gene promoter sequences activates transcription of the MICA gene from its endogenous locus. Inhibiting microRNA function, which targets the 3' untranslated region of the MICA gene, enhances this activation. These results demonstrate that the combination of Cas9-based transcriptional activators and simultaneous modulation of microRNA function may be a powerful tool for enhancing MICA protein expression and efficient anti-pathogenic cell immunity.
Collapse
Affiliation(s)
- Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Mari Yamagami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Tatsunori Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoko Ohno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
28
|
Gam R, Shah P, Crossland RE, Norden J, Dickinson AM, Dressel R. Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes. Front Immunol 2017; 8:380. [PMID: 28421078 PMCID: PMC5377073 DOI: 10.3389/fimmu.2017.00380] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 03/16/2017] [Indexed: 12/18/2022] Open
Abstract
The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP–mRNA–miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.
Collapse
Affiliation(s)
- Rihab Gam
- Hematological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Pranali Shah
- Institute of Cellular and Molecular Immunology, University Medical Centre Göttingen, Göttingen, Germany
| | - Rachel E Crossland
- Hematological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Jean Norden
- Hematological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Anne M Dickinson
- Hematological Sciences, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Ralf Dressel
- Institute of Cellular and Molecular Immunology, University Medical Centre Göttingen, Göttingen, Germany
| |
Collapse
|
|
29
|
Kishikawa T, Otsuka M, Ohno M, Yoshikawa T, Sato M, Koike K. Development of a screening method to identify regulators of MICA shedding. Biochem Biophys Res Commun 2015; 465:764-768. [PMID: 26299929 DOI: 10.1016/j.bbrc.2015.08.081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 08/19/2015] [Indexed: 12/27/2022]
Abstract
Immune cells, such as natural killer (NK) cells, recognize virally infected and transformed cells, and eliminate them through the interaction between NKG2D receptors on NK cells and NKG2D ligands on pathogenic cells. Shedding of NKG2D ligands is thought to be a type of counter-mechanism employed by pathogenic cells to evade from NKG2D-mediated immune surveillance. MHC class I polypeptide-related sequence A (MICA) is a prototypical NKG2D ligand. We previously reported that, in soluble form, MICA expression levels are significantly associated with hepatitis virus-induced hepatocellular carcinoma. Here, we report a MICA shedding assay that utilizes membrane-bound MICA tagged at its N-terminus with a nano-luciferase reporter to quantify MICA shedding into culture media. Using this method, we screened a compound library and identified putative regulators of MICA shedding that have the potential to enhance the immune reaction by simultaneously increasing cell surface MICA levels and decreasing soluble MICA levels. This shedding assay may be useful for screening regulators of cell surface molecule shedding.
Collapse
Affiliation(s)
- Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama 332-0012, Japan.
| | - Motoko Ohno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takeshi Yoshikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| |
Collapse
|
|
30
|
Peng G, Yuan X, Yuan J, Liu Q, Dai M, Shen C, Ma J, Liao Y, Jiang W. miR-25 promotes glioblastoma cell proliferation and invasion by directly targeting NEFL. Mol Cell Biochem 2015. [PMID: 26209061 DOI: 10.1007/s11010-015-2516-x] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Glioblastoma multiforme (GBM) is the most malignant and common brain tumor; it is aggressive growth pattern means that GBM patients face a poor prognosis even when receiving the best available treatment modalities. In recent years, an increasing number of reports suggest that the discovery of microRNAs (miRNAs) might provide a novel therapeutic target for human cancers, including GBM. One miRNA in particular, microRNA-25 (miR-25), is overexpressed in several cancers, wherein accumulating evidence indicates that it functions as an oncogene. However, the function of miR-25 in GBM has not been totally elucidated. In this study, we demonstrated that miR-25 was significantly up-regulated in astrocytoma tissues and glioblastoma cell lines. In vitro studies further demonstrated that overexpressed miR-25 was able to promote, while its antisense oligos inhibited cell proliferation and invasion in U251 cells. Moreover, we identified neurofilament light polypeptide (NEFL) as a novel target molecule of miR-25. Also of note was the fact that NEFL was down-regulated with increased levels of miR-25 expression in human astrocytoma clinical specimens. In addition, via the mTOR signaling pathway, NEFL-siRNA could significantly attenuate the inhibitory effects of knockdown miR-25 on the proliferation and invasion of U251 cells. Overall, our results showed an important role for miR-25 in regulating NEFL expression in GBM, and suggest that miR-25 could be a potential target for GBM treatment.
Collapse
Affiliation(s)
- Gang Peng
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Xianrui Yuan
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Jian Yuan
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Qing Liu
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Minhui Dai
- Department of Ophthalmology, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Chenfu Shen
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Jianrong Ma
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Yiwei Liao
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China
| | - Weixi Jiang
- Department of Neurosurgery, Xiangya Hospital of Central South University, 87 XiangYa Road, Changsha, 410008, Hunan, China.
| |
Collapse
|
|
31
|
Kishikawa T, Otsuka M, Tan PS, Ohno M, Sun X, Yoshikawa T, Shibata C, Takata A, Kojima K, Takehana K, Ohishi M, Ota S, Noyama T, Kondo Y, Sato M, Soga T, Hoshida Y, Koike K. Decreased miR122 in hepatocellular carcinoma leads to chemoresistance with increased arginine. Oncotarget 2015; 6:8339-8352. [PMID: 25826076 PMCID: PMC4480756 DOI: 10.18632/oncotarget.3234] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 01/28/2015] [Indexed: 12/12/2022] Open
Abstract
Reduced expression of microRNA122 (miR122), a liver-specific microRNA, is frequent in hepatocellular carcinoma (HCC). However, its biological significances remain poorly understood. Because deregulated amino acid levels in cancers can affect their biological behavior, we determined the amino acid levels in miR122-silenced mouse liver tissues, in which intracellular arginine levels were significantly increased. The increased intracellular arginine levels were through upregulation of the solute carrier family 7 (SLC7A1), a transporter of arginine and a direct target of miR122. Arginine is the substrate for nitric oxide (NO) synthetase, and intracellular NO levels were increased in miR122-silenced HCC cells, with increased resistance to sorafenib, a multikinase inhibitor. Conversely, maintenance of the miR122-silenced HCC cells in arginine-depleted culture media, as well as overexpression of miR122 in miR122-low-expressing HCC cells, reversed these effects and rendered the cells more sensitive to sorafenib. Using a reporter knock-in construct, chemical compounds were screened, and Wee1 kinase inhibitor was identified as upregulators of miR122 transcription, which increased the sensitivity of the cells to sorafenib. These results provide an insight into sorafenib resistance in miR122-low HCC, and suggest that arginine depletion or a combination of sorafenib with the identified compound may provide promising approaches to managing this HCC subset.
Collapse
Affiliation(s)
- Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
- Japan Science and Technology Agency, PRESTO, Kawaguchi,
Saitama 332–0012, Japan
| | - Poh Seng Tan
- Liver Cancer Program, Tisch Cancer Institute, Division of
Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY
10029, USA
- Division of Gastroenterology and Hepatology, University
Medicine Cluster, National University Health System, 119228, Singapore
| | - Motoko Ohno
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Xiaochen Sun
- Liver Cancer Program, Tisch Cancer Institute, Division of
Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY
10029, USA
| | - Takeshi Yoshikawa
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Chikako Shibata
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Akemi Takata
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Kentaro Kojima
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Kenji Takehana
- Pharmacology Research Laboratory, Research Institute,
Ajinomoto Pharmaceutical Co., Ltd., Kawasaki, Kanagawa 210–8681, Japan
| | - Maki Ohishi
- Institute for Advanced Biosciences, Keio University, Tsuruoka,
Yamagata 997–0052, Japan
| | - Sana Ota
- Institute for Advanced Biosciences, Keio University, Tsuruoka,
Yamagata 997–0052, Japan
| | - Tomoyuki Noyama
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Yuji Kondo
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| | - Tomoyoshi Soga
- Pharmacology Research Laboratory, Research Institute,
Ajinomoto Pharmaceutical Co., Ltd., Kawasaki, Kanagawa 210–8681, Japan
| | - Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of
Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY
10029, USA
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine,
The University of Tokyo, Tokyo 113–8655, Japan
| |
Collapse
|
|
32
|
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death globally. Above well-known risk factors for HCC development ranging from various toxins to diseases such as diabetes mellitus, chronic infection with hepatitis B virus and hepatitis C virus (HCV) poses the most serious threat, constituting the cause in more than 80 % of cases. In addition to the viral genes intensively investigated, the pathophysiological importance of host genetic factors has also been greatly and increasingly appreciated. Genome-wide association studies (GWAS) comprehensively search the host genome at the single-nucleotide level, and have successfully identified the genomic region associated with a whole variety of diseases. With respect to HCC, there have been reports from several groups on single nucleotide polymorphisms (SNPs) associated with hepatocarcinogenesis, among which was our GWAS discovering MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for HCV-induced HCC. MICA is a natural killer (NK) group 2D (NKG2D) ligand, whose interaction with NKG2D triggers NK cell-mediated cytotoxicity toward the target cells, and is a key molecule in tumor immune surveillance as its expression is induced on stressed cells such as transformed tumor cells for the detection by NK cells. In this review, the latest understanding of the MICA-NKG2D system in viral HCC, particularly focused on its antitumor properties and the involvement of MICA SNPs, is summarized, followed by a discussion of targets for state-of-the-art cancer immunotherapy with personalized medicine in view.
Collapse
|
|
33
|
Qian J, Li R, Wang YY, Shi Y, Luan WK, Tao T, Zhang JX, Xu YC, You YP. MiR-1224-5p acts as a tumor suppressor by targeting CREB1 in malignant gliomas. Mol Cell Biochem 2015; 403:33-41. [DOI: 10.1007/s11010-015-2334-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Accepted: 01/16/2015] [Indexed: 12/23/2022]
|
|
34
|
Ohno M, Otsuka M, Kishikawa T, Shibata C, Yoshikawa T, Takata A, Muroyama R, Kowatari N, Sato M, Kato N, Kuroda S, Koike K. Specific delivery of microRNA93 into HBV-replicating hepatocytes downregulates protein expression of liver cancer susceptible gene MICA. Oncotarget 2014; 5:5581-5590. [PMID: 25026299 PMCID: PMC4170619 DOI: 10.18632/oncotarget.2143] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2014] [Accepted: 06/24/2014] [Indexed: 01/05/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC). To date, the lack of efficient in vitro systems supporting HBV infection and replication has been a major limitation of HBV research. Although primary human hepatocytes support the complete HBV life cycle, their limited availability and difficulties with gene transduction remain problematic. Here, we used human primary hepatocytes isolated from humanized chimeric uPA/SCID mice as efficient sources. These hepatocytes supported HBV replication in vitro. Based on analyses of mRNA and microRNA (miRNA) expression levels in HBV-infected hepatocytes, miRNA93 was significantly downregulated during HBV infection. MiRNA93 is critical for regulating the expression levels of MICA protein, which is a determinant for HBV-induced HCC susceptibility. Exogenous addition of miRNA93 in HBV-infected hepatocytes using bionanocapsules consisted of HBV envelope L proteins restored MICA protein expression levels in the supernatant. These results suggest that the rescued suppression of soluble MICA protein levels by miRNA93 targeted to HBV-infected hepatocytes using bionanocapsules may be useful for the prevention of HBV-induced HCC by altering deregulated miRNA93 expression.
Collapse
Affiliation(s)
- Motoko Ohno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Japan Science and Technology Agency, PRESTO, Kawaguchi, Saitama, Japan
| | - Takahiro Kishikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Chikako Shibata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takeshi Yoshikawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akemi Takata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Muroyama
- Unit of Disease Control Genome Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Norie Kowatari
- Unit of Disease Control Genome Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Masaya Sato
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Naoya Kato
- Unit of Disease Control Genome Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shun'ichi Kuroda
- Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
35
|
Tan W, Li Y, Lim SG, Tan TMC. miR-106b-25/miR-17-92 clusters: Polycistrons with oncogenic roles in hepatocellular carcinoma. World J Gastroenterol 2014; 20:5962-5972. [PMID: 24876719 PMCID: PMC4033436 DOI: 10.3748/wjg.v20.i20.5962] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 01/11/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
MicroRNAs are small endogenously expressed RNA molecules which are involved in the process of silencing gene expression through translational regulation. The polycistronic miR-17-92 cluster is the first microRNA cluster shown to play a role in tumorigenesis. It has two other paralogs in the human genome, the miR-106b-25 cluster and the miR-106a-363 cluster. Collectively, the microRNAs encoded by these clusters can be further grouped based on the seed sequences into four families, namely the miR-17, the miR-92, the miR-18 and the miR-19 families. Over-expression of the miR-106b-25 and miR-17-92 clusters has been reported not only during the development of cirrhosis but also subsequently during the development of hepatocellular carcinoma. Members of these clusters have also been shown to affect the replication of hepatitis B and hepatitis C viruses. Various targets of these microRNAs have been identified, and these targets are involved in tumor growth, cell survival and metastasis. In this review, we first describe the regulation of these clusters by c-Myc and E2F1, and how the members of these clusters in turn regulate E2F1 expression forming an auto-regulatory loop. In addition, the roles of the various members of the clusters in affecting relevant target gene expression in the pathogenesis of hepatocellular carcinoma will also be discussed.
Collapse
|
|
36
|
Frau M, Feo CF, Feo F, Pascale RM. New insights on the role of epigenetic alterations in hepatocellular carcinoma. J Hepatocell Carcinoma 2014; 1:65-83. [PMID: 27508177 PMCID: PMC4918272 DOI: 10.2147/jhc.s44506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Emerging evidence assigns to epigenetic mechanisms heritable differences in gene function that come into being during cell development or via the effect of environmental factors. Epigenetic deregulation is strongly involved in the development of hepatocellular carcinoma (HCC). It includes changes in methionine metabolism, promoter hypermethylation, or increased proteasomal degradation of oncosuppressors, as well as posttranscriptional deregulation by microRNA or messenger RNA (mRNA) binding proteins. Alterations in the methylation of the promoter of methyl adenosyltransferase MAT1A and MAT2A genes in HCC result in decreased S-adenosylmethionine levels, global DNA hypomethylation, and deregulation of signal transduction pathways linked to methionine metabolism and methyl adenosyltransferases activity. Changes in S-adenosylmethionine levels may also depend on MAT1A mRNA destabilization associated with MAT2A mRNA stabilization by specific proteins. Decrease in MAT1A expression has also been attributed to miRNA upregulation in HCC. A complex deregulation of miRNAs is also strongly involved in hepatocarcinogenesis, with up-regulation of different miRNAs targeting oncosuppressor genes and down-regulation of miRNAs targeting genes involved in cell-cycle and signal transduction control. Oncosuppressor gene down-regulation in HCC is also induced by promoter hypermethylation or posttranslational deregulation, leading to proteasomal degradation. The role of epigenetic changes in hepatocarcinogenesis has recently suggested new promising therapeutic approaches for HCC on the basis of the administration of methylating agents, inhibition of methyl adenosyltransferases, and restoration of the expression of tumor-suppressor miRNAs.
Collapse
Affiliation(s)
- Maddalena Frau
- Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| | - Claudio F Feo
- Department of Clinical and Experimental Medicine, Division of Surgery, University of Sassari, Sassari, Italy
| | - Francesco Feo
- Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| | - Rosa M Pascale
- Department of Clinical and Experimental Medicine, Division of Experimental Pathology and Oncology, University of Sassari, Sassari, Italy
| |
Collapse
|